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It’s well-known that the National Institutes of Health (NIH) offers billions of dollars in grants to US academic research facilities. What’s less well-known is that each year, hundreds of new inventions are produced in the laboratories of NIH, the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA), and these inventions are licensed out to private companies in the US and internationally for further research and development, with the hopes of bringing new products to market.

RAPS’ members-only online community, Regulatory Exchange or “RegEx” as it is often called, was recently named one of three “Most Successful Community” award winners of 2016 by Higher Logic. RegEx is built on the Higher Logic platform.

The guideline applies to non-recombinant biologics, such as heparins, gonadotrophins and urokinase, with EMA explaining that its creation was spurred by a desire to better control the manufacturing process and ultimate quality of the products to ensure their safety and efficacy.

At its core, the guideline calls for manufacturers to "clearly define" where the manufacturing process starts, and provide all relevant information to regulators through the dossier.

Definition Problems

The problem, regulators continued, is that when products - heparin for example - undergo multi-source processing, the final product is subject to the quality control processes of each of the respective starting materials. Without full access to the original manufacturing data, the finished product manufacturer will not be able to attest to the quality of the finished product, and neither will regulators.

"Such variability is triggered by the high demand for the starting material and consequential manufacturing and market logistics. For some non-recombinant products such as heparins or its derivatives there is an increasing difficulty in finding starting materials suppliers," EMA wrote.

And given the multi-step manufacturing processes, EMA said manufacturers have been using different definitions of the term "starting materials," resulting in the need for a single definition to be used.

New Definitions

As a basic starting point, EMA said marketing authorization dossiers should include "information that adequately describes the manufacturing process and process controls.

"All materials needed in order to manufacture the active substance(s) shall be listed, identifying where each material is used in the process," EMA continued. "Information on quality and control of all starting materials and process reagents used in the manufacture of an active substance should be provided."

EMA notes that marketing authorization holders (MAHs) must have full access to the active substance manufacturing data for any biological medicinal product.

Per Directive 2001/83/EC, the term "starting materials" is taken to mean "any substance of biological origin such as micro-organisms, organs and tissues of either plant or animal origin, cells or fluids (including blood or plasma) of human or animal origin, and biotechnological cell constructs (cell substrates, whether they are recombinant or not, including primary cells)."

This definition will also apply to process intermediates as well, which are defined as a "substance produced during steps of the processing of the active substance that undergoes further molecular change or purification before it becomes the active substance."

However, other substances used in the manufacturing of the active substance - reagents, culture media, additives, buffers, etc - but from which an active substance is not directly derived are defined as raw materials, and are not considered a starting material.

This definition can become more complicated when dealing with tissues or fluids, particularly when dealing with very early active substances, the guideline explains. When various intermediates are used from various sources, manufacturers will have a more difficult time obtaining the quality attributes of each respective intermediate as well as proving their comparability.

"Thus, if a manufacturer decides to use starting materials or intermediates from different sources and / or a different manufacturing process for the early production steps it should be shown that comparable active substances are consistently obtained in terms of relevant quality attributes irrespective of the process applied," EMA added.

The guideline concludes by noting that good manufacturing practice agreements should be in place between any sponsor and a contract manufacturer and "clearly defined" in a Quality Agreement.

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